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| United States Patent |
5,043,343
|
|
Wyman
|
August 27, 1991
|
Certain 5-substituted-1-aza-bicyclo[3.3.3]heptanes and their
pharmaceutical compositions and methods
Abstract
A compound of formula (I) or a pharmaceutically acceptable salt thereof:
##STR1##
in which Z is a heterocyclic group
##STR2##
in which Q represents a 3-membered divalent residue completing a
5-membered aromatic ring and comprises one or two heteroatoms selected
from oxygen, nitrogen and sulphur, or three nitrogen atoms, any amino
nitrogen being substituted by a C.sub.1-2 alkyl, cyclopropyl or propargyl
group, and any ring carbon atom being optionally substituted by a group
R.sub.1 ; or a group
##STR3##
in which A.sub.1, A.sub.2 and A.sub.3 complete a 5-membered aromatic ring
and A.sub.1 is oxygen or sulphur, one of A.sub.2 and A.sub.3 is CR.sub.2
and the other is nitrogen or CR.sub.3, or A.sub.2 is oxygen or sulphur,
one of A.sub.1 and A.sub.3 is CR.sub.2 and the other is CR.sub.3 ; and
R.sub.1, R.sub.2 and R.sub.3 are independently selected from hydrogen,
halogen, CN, OR.sub.4, SR.sub.4, N(R.sub.4).sub.2, NHCOR.sub.4,
NHCOOCH.sub.3, NHCOOC.sub.2 H.sub.5, NHOR.sub.4, NHNH.sub.2, NO.sub.2,
COR.sub.4, COR.sub.5, cyclopropyl, C.sub.2-5 straight chain alkenyl,
C.sub.2-5 straight chain alkynyl or C.sub.1-5 straight chain alkyl
optionally terminally substituted with OR.sub.4, N(R.sub.4).sub.2,
SR.sub.4, CO.sub.2 R.sub.4, CON(R.sub.4).sub.2 or one, two or three
halogen atoms, in which each R.sub.4 is independently hydrogen or
C.sub.1-3 alkyl and R.sub.5 is OR.sub.4, NH.sub.2 or NHR.sub.4 ;
or in which Z is a group --C(R.sub.7).dbd.NR.sub.6 in which R.sub.6 is a
group OR.sub.8, where R.sub.8 is C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, a group OCOR.sub.9 where R.sub.9 is hydrogen or
R.sub.8, or a group NHR.sub.10 or NR.sub.11 R.sub.12 where R.sub.10,
R.sub.11 and R.sub.12 are independently C.sub.1-2 alkyl and R.sub.7 is
hydrogen or C.sub.1-4 alkyl, subject to the proviso that when R.sub.6 is a
group OCOR.sub.9 or NHR.sub.10, R.sub.7 is C.sub.1-4 alkyl.
| Inventors:
|
Wyman; Paul A. (Harlow, GB2)
|
| Assignee:
|
Beecham Group p.l.c. (Brentford, GB2)
|
| Appl. No.:
|
566980 |
| Filed:
|
August 14, 1990 |
Foreign Application Priority Data
| Aug 16, 1989[GB] | 8918658 |
| Aug 16, 1989[GB] | 8918659 |
| Feb 28, 1990[GB] | 9004437 |
| Current U.S. Class: |
514/299; 546/112 |
| Intern'l Class: |
A61K 031/44; C07D 471/08 |
| Field of Search: |
546/112
514/299
|
References Cited
U.S. Patent Documents
| 4988706 | Jan., 1991 | Hadley et al. | 514/299.
|
| Foreign Patent Documents |
| 0239309 | Sep., 1987 | EP.
| |
| 0287356 | Sep., 1988 | EP.
| |
| 0307141 | Mar., 1989 | EP.
| |
| 0307142 | Mar., 1989 | EP.
| |
| 0316718 | May., 1989 | EP.
| |
| 0323864 | Jul., 1989 | EP.
| |
| 0338723 | Oct., 1989 | EP.
| |
| 0339834 | Nov., 1989 | EP.
| |
| 0366304 | May., 1990 | EP.
| |
| 0398616 | Nov., 1990 | EP.
| |
| 0398617 | Nov., 1990 | EP.
| |
| 0402056 | Dec., 1990 | EP.
| |
Primary Examiner: Dentz; Bernard
Attorney, Agent or Firm: Hopgood, Calimafde, Kalil, Blaustein & Judlowe
Claims
I claim:
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
##STR36##
in which Z is a heterocyclic group
##STR37##
in which Q represents a 3-membered divalent residue completing a
5-membered aromatic ring and comprises one or two heteroatoms selected
from oxygen, nitrogen and sulphur, or three nitrogen atoms, any amino
nitrogen being substituted by a C.sub.1 -C.sub.2 alkyl, cyclopropyl or
propargyl group, and any ring carbon atom being optionally substituted by
a group R.sub.1 ; or a group
##STR38##
in which A.sub.1, A.sub.2 and A.sub.3 complete a 5-membered aromatic ring
and A.sub.1 is oxygen or sulphur, one of A.sub.2 and A.sub.3 is CR.sub.2
and the other is nitrogen or CR.sub.3, or A.sub.2 is oxygen or sulphur,
one of A.sub.1 and A.sub.3 is CR.sub.2 and the other is CR.sub.3; and
R.sub.1, R.sub.2 and R.sub.3 are independently selected from hydrogen,
halogen, CN, OR.sub.4, SR.sub.4, N(R.sub.4).sub.2, NHCOR.sub.4,
NHCOOCH.sub.3, NHCOOC.sub.2 H.sub.5, NHOR.sub.4, NHNH.sub.2, NO.sub.2,
COR.sub.4, COR.sub.5, cyclopropyl, C.sub.2-5 straight chain alkenyl,
C.sub.2-5 straight chain alkynyl or C.sub.1-5 straight chain alkyl
optionally terminally substituted with OR.sub.4, N(R.sub.4).sub.2,
SR.sub.4, CO.sub.2 R.sub.4, CON(R.sub.4).sub.2 or one, two or three
halogen atoms, in which each R.sub.4 is independently hydrogen or
C.sub.1-3 alkyl and R.sub.5 is OR.sub.4, NH.sub.2 or NHR.sub.4 ;
or in which Z is a group --C(R.sub.7).dbd.NR.sub.6 in which R.sub.6 is a
group OR.sub.8, where R.sub.8 is C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, a group OCOR.sub.9 where R.sub.9 is hydrogen or
R.sub.8, or a group NHR.sub.10 or NR.sub.11 R.sub.12 where R.sub.10,
R.sub.11 and R.sub.12 are independently C.sub.1-2 alkyl and R.sub.7 is
hydrogen or C.sub.1-4 alkyl, subject to the proviso that when R.sub.6 is a
group OCOR.sub.9 or NHR.sub.10, R.sub.7 is C.sub.1-4 alkyl.
2. A compound according to claim 1 in which the 5-membered aromatic ring in
Z is an oxadiazole, oxazole, thiadiazole, thiazole, furan, triazole or
tetrazole ring.
3. A compound according to claim 1 in which R.sub.1, R.sub.2 and R.sub.3
are independently selected from hydrogen, halogen, N(R.sub.4.sup.1).sub.2
in which each R.sub.4.sup.1 is independently hydrogen or methyl, straight
chain C.sub.2-3 alkenyl, straight chain C.sub.2-3 alkynyl, cyclopropyl or
straight chain C.sub.1-5 alkyl optionally terminally substituted with
OR.sub.4.sup.2 or one, two or three fluorine atoms, in which R.sub.4.sup.2
is methyl.
4. A compound according to claim 1 in which R.sub.6 is methoxy, ethoxy,
alkyloxy, propargyloxy, acetoxy or dimethylamino.
5. A compound according to claim 4 in which R.sub.7 is hydrogen or methyl.
6. 5-(3-Amino-1,2,4-oxadiazol-5-yl)-1-azabicyclo[3.1.1]heptane.
5-(3-methyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo[3.1.1]heptane,
5-(1,3-oxazol-5-yl)-1-azabicyclo[3.1.1]heptane,
5-(1,3-oxazol-2-yl)-1-azabicyclo[3.1.1]heptane,
5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo[3.1.1]heptane,
5-(3-propyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo[3.1.1]heptane,
5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo[3.1.1]heptane,
5-(3-butyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo[3.1 1]heptane,
5-(3-methoxymethyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo[3.1.1]heptane,
5-(3-pentyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo[3.1.1]heptane,
E-5-(3-but-2-enyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo[3.1.1]heptane,
5-(fur-2-yl)-1-azabicyclo[3.1.1]heptane,
5-(2-methyl-1,3,4-oxadiazol-5-yl)-1-azabicyclo[3.1.1]heptane,
E-1-azabicyclo[3.1.1]hept-5-ylcarboxaldehyde-O-methyloxime or
E and Z-5-acetyl-1-azabicyclo[3.1.1heptane O-methyl-oxime, or a
pharmaceutically acceptable salt of any of the foregoing compounds.
7. A pharmaceutical composition which comprises a compound according to
claim 1 and a pharmaceutically acceptable carrier.
8. A method of treatment and/or prophylaxis of dementia in mammals
including humans, which comprises administering to the sufferer an
effective amount of a compound according to claim 1.
Description
This invention relates to compounds having pharmaceutical activity, to a
process for their preparation and their use as pharmaceuticals.
EP-A-0287356 discloses certain substituted 1-azabicyclic compounds which
enhance acetylcholine function via an action at muscarinic receptors
within the central nervous system.
A novel group of compounds has been discovered which also enhance
acetylcholine function via an action at muscarinic receptors within the
central nervous system and are therefore of potential use in the treatment
and/or prophylaxis of dementia in mammals.
According to the present invention, there is provided a compound of formula
(I) or a pharmaceutically acceptable salt thereof:
##STR4##
in which Z is a heterocyclic group
##STR5##
in which Q represents a 3-membered divalent residue completing a
5-membered aromatic ring and comprises one or two heteroatoms selected
from oxygen, nitrogen and sulphur, or three nitrogen atoms, any amino
nitrogen being substituted by a C.sub.1-2 alkyl, cyclopropyl or propargyl
group, and any ring carbon atom being optionally substituted by a group
R.sub.1 ; or a group
##STR6##
in which A.sub.1, A.sub.2 and A.sub.3 complete a 5-membered aromatic ring
and A.sub.1 is oxygen or sulphur, one of A.sub.2 and A.sub.3 is CR.sub.2
and the other is nitrogen or CR.sub.3, or A.sub.2 is oxygen or sulphur,
one of A.sub.1 and A.sub.3 is CR.sub.2 and the other is CR.sub.3 ; and
R.sub.1, R.sub.2 and R.sub.3 are independently selected from hydrogen,
halogen, CN, OR.sub.4, SR.sub.4, N(R.sub.4).sub.2, NHCOR.sub.4,
NHCOOCH.sub.3, NHCOOC.sub.2 H.sub.5, NHOR.sub.4, NHNH.sub.2, NO.sub.2,
COR.sub.4, COR.sub.5, cyclopropyl, C.sub.2-5 straight chain alkenyl,
C.sub.2-5 straight chain alkynyl or C.sub.2-5 straight chain alkyl
optionally terminally substituted with OR.sub.4, N(R.sub.4).sub.2,
SR.sub.4, CO.sub.2 R.sub.4, CON(R.sub.4).sub.2 or one, two or three
halogen atoms, in which each R.sub.4 is independently hydrogen or C.sub.
1-3 alkyl and R.sub.5 is OR.sub.4, NH.sub.2 or NHR.sub.4 ;
or in which Z is a group --C(R.sub.7).dbd.NR.sub.6 in which R.sub.6 is a
group OR.sub.8, where R.sub.8 is C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, a group OCOR.sub.9 where R.sub.9 is hydrogen or
R.sub.8, or a group NHR.sub.10 or NR.sub.11 R.sub.12 where R.sub.10,
R.sub.11 and R.sub.12 are independently C.sub.1-2 alkyl and R.sub.7 is
hydrogen or C.sub.1-4 alkyl, subject to the proviso that when R.sub.6 is a
group OCOR.sub.9 or NHR.sub.10, R.sub.7 is C.sub.1-4 alkyl.
The term halogen includes bromine, chlorine and fluorine.
Compounds of formula (I) in which Z is --C(R.sub.7).dbd.NR.sub.6 are
capable of existing as geometric isomers. The invention extends to each of
these stereoisomeric forms, and to mixtures thereof. The different
stereoisomeric forms may be separated one from the other by the usual
methods, or any given isomer may be obtained by stereospecific synthesis.
The compounds of formula (I) can form acid addition salts with acids, such
as the conventional pharmaceutically acceptable acids, for example
hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric,
lactic, mandelic, tartaric, oxalic and methanesulphonic.
5-Membered aromatic heterocycles within the definition of variable Z
include oxadiazole such as 1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl and
1,3,4-oxadiazol-2-yl, oxazole such as 1,3-oxazol-2-yl, 1,3-oxazol-4-yl
1,3-oxazol-5-yl, 1,2-oxazol-3-yl and 1,2-oxazol-5-yl, thiadiazole such as
1,2,4-thiadiazol-5-yl and 1,3,4-thiadiazol-2-yl, thiazole such as
1,3-thiazol-2-yl, 1,3-thiazol-5-yl and 1,2-thiazol-5-yl, furan such as
furan-2-yl and furan-3-yl, triazole such as 1-alkyl-, 2-alkyl- or 3-alkyl-
1,2,3-triazol-4-yl and 1,2,4-triazol-3-yl including
1-alkyl-1,2,4-triazol-3-yl, 1-alkyl-tetrazol-5-yl and
2-alkyl-tetrazol-5-yl, where `alkyl` signifies a C.sub.1-2 alkyl,
cyclopropyl or propargyl group.
In a preferred aspect, variables R.sub.1, R.sub.2 and R.sub.3 are
independently selected from hydrogen, halogen, N(R.sub.4.sup.1).sub.2 in
which each R.sub.4.sup.1 is independently hydrogen or methyl, straight
chain C.sub.2-3 alkenyl, straight chain C.sub.2-3 alkynyl, cyclopropyl or
straight chain C.sub.1-5 alkyl optionally terminally substituted with
OR.sub.4.sup.2 or one, two or three fluorine atoms, in which R.sub.4.sup.2
is methyl.
Values for R.sub.1, R.sub.2 and R.sub.3 include hydrogen, methyl,
methoxymethyl, ethyl, n-propyl, n-butyl, n-pentyl, cyclopropyl,
but-2-enyl, NH.sub.2 and CH.sub.2 F, preferably hydrogen, methyl, ethyl,
n-propyl, n-butyl and n-pentyl.
It will be appreciated that the range of values for R.sub.1, R.sub.2 and
R.sub.3 will be limited by the preparative constraints and/or stability of
the group Z. For example, an oxazole ring will tolerate a 2-amino
substituent whereas 2-amino-furans are unstable. Conversely, 2-halo-furans
are stable whereas 2-halo-oxazoles are very labile compounds. Where Z is a
tri- or tetrazole group, the amino nitrogen must be substituted,
preferably Y to the position of the azabicyclic moiety.
Examples of heterocyclic Z include 3-amino-1,2,4-oxadiazol-5-yl,
3-methyl-1,2,4-oxadiazol-5-yl, 1,3-oxazol-5-yl, 1,3-oxazol-2-yl,
3-ethyl-1,2,4-oxadiazol-5-yl, 3-propyl-1,2,4-oxadiazol-5-yl,
3-cyclopropyl-1,2,4-oxadiazol-S-yl, 3-butyl-1,2,4-oxadiazol-5-yl,
3-methoxymethyl-1,2,4-oxadiazol-5-yl, 3-pentyl-1,2,4-oxadiazol-5-yl,
3-but-2-enyl-1,2,4-oxadiazol-5-yl, fur-2-yl and
2-methyl-1,3,4-oxadiazol-5-yl.
The groups R.sub.8 and R.sub.9 in R.sub.6 are preferably selected from
methyl, ethyl, allyl and propargyl. R.sub.10, R.sub.11 and R.sub.12 are
preferably methyl. Suitable examples of R.sub.6 include methoxy, ethoxy,
allyloxy, propargyloxy, acetoxy and dimethylamino.
When R.sub.6 is a group OR.sub.8 or NR.sub.11 R.sub.12, R.sub.7 is
preferably hydrogen or methyl.
When R.sub.6 is a group OCOR.sub.9 or NHR.sub.10, R.sub.7 is preferably
methyl.
The invention also provides a process for the preparation of a compound of
formula (I), or a pharmaceutically acceptable salt thereof, which process
comprises cyclising a compound of formula (II):
##STR7##
in which A represents Z or an electron withdrawing group convertible
thereto, L is a leaving group and R.sub.13 represents hydrogen or an
N-protecting group,
and thereafter, optionally or as necessary, removing any R.sub.13
protecting group, converting A to Z, interconverting Z and/or forming a
pharmaceutically acceptable salt.
Examples of the N-protecting group R.sub.13 include benzyl and substituted
benzyl. However, it is greatly preferred that R.sub.13 is hydrogen.
Examples of the leaving group L include halo such as chloro.
Examples of A include C.sub.1-4 alkoxycarbonyl and cyano, most preferably
C.sub.1-4 alkoxycarbonyl.
The cyclisation is preferably effected in a suitable solvent such as
isopropanol under basic conditions at elevated temperature.
Conversion of A to a group Z, as defined for formula (I), may be carried
out using procedures as described in, for example standard text books on
heterocyclic chemistry such as `Comprehensive Heterocyclic Chemistry`, A.
R. Katritzky and C. W. Rees, Pergamon, 1984.
The A group is first converted, as necessary, to a suitable starting group
Z' for the chosen conversion reaction to give the required group Z.
A Z' carboxy group may be obtained by conventional de-esterification of an
A alkoxycarbonyl group.
A Z' chlorocarbonyl group may be obtained by treatment of a Z' carboxy
group by conventional routes under appropriate conditions.
A Z' aminocarbonyl group may be obtained by treatment of a Z'
chlorocarbonyl or, more preferably, an alkoxycarbonyl group with ammonia.
A Z' cyano group may be obtained by treatment of a Z' aminocarbonyl group
with a dehydrating agent such as phosphorus pentoxide in toluene or
trifluoroacetic acid anhydride in tetrahydrofuran and pyridine.
A Z' alkylcarbonyl group may be obtained from an A cyano group by treatment
with the appropriate alkyl lithium in ether at depressed temperature, or
by treatment of a LiOOC group with the appropriate alkyl lithium, the
LiOOC group being obtained by hydrolysis of an A alkoxycarbonyl group with
lithium hydroxide in water. Alternatively and less preferably, a Z'
alkylcarbonyl group may be obtained by reaction of a Z' chlorocarbonyl
group with N,O-dimethylhydroxylamine and treatment with an alkyl lithium
or Grignard reagent.
A Z' bromomethylcarbonyl group may be obtained by treatment of a Z'
COCH.sub.3 group either with bromine in a suitable solvent such as
methanol, the nitrogen of the azabicycle being protected as the
hydrochloride or hydrobromide salt, or with lithium diisopropylamide and
trimethylsilyl chloride at low temperature followed by N-bromosuccinimide
in tetrahydrofuran at low temperature. Alternatively and less preferably,
a Z' --COCl group may be converted to a --COCH.sub.2 Br group by treatment
with diazomethane in ether at low temperature followed by hydrogen bromide
in acetic acid at ambient temperature.
A Z' formyl group may be obtained by conventional reduction of an A
alkoxycarbonyl group with a reducing agent such as diisobutylaluminium
hydride in an inert solvent such as toluene at low temperature, or,
alternatively and less preferably, hydrolysis with acid, followed by
conversion to the acid chloride and reaction with O-N-methylated dimethyl
hydroxylamine hydrochloride in the presence of pyridine in a suitable
solvent such as dichloromethane to give the O-N-dimethyl amide. Reduction
with diisobutyl aluminium hydride under similar conditions as above yields
the required formyl group.
A Z' CH.sub.2 N.sup.+ .tbd.C.sup.- group may be obtained from a
formamidomethyl group by treatment with phosgene and triethylamine. The
formamidomethyl group may in turn be obtained from the aminomethyl group
by reaction with an ester of formic acid such as ethyl formate. The
aminomethyl group may be obtained by reduction of the aminocarbonyl group
with lithium aluminium hydride.
When Z represents a 1,2,3-triazol-4-yl group, a Z' formyl group may be
treated with triphenyl phosphine, carbon tetrabromide and zinc in an inert
solvent such as dichloromethane at ambient temperature to provide a
2,2-dibromoethenyl group which may be eliminated with n-butyl lithium in
hexane to give an ethynyl group. Treatment of the latter with
azidotrimethyl silane in an inert solvent such as tetrahydrofuran at
elevated temperature followed by lower alcohol at ambient temperature
yields the unsubstituted 1,2,3-triazol-4-yl group which is alkylated as
required. A 2-alkyl group may be introduced by treatment with the
corresponding diazoalkane in ether at ambient temperature.
Alternatively a Z' acetyl group may be successively treated with hydrogen
chloride, chlorine and triphenylphosphine to yield a
triphenylphosphinemethylenecarbonyl group which may be treated with
m-nitrobenzoyl azide in acetonitrile at elevated temperature to yield the
1,2,3-triazol-4-yl group which is protected at the 1 position by
m-nitrobenzoyl. The protecting group may be removed by prolonged heating
in a lower alcohol, by treatment with ammonia or by chromatography on
basic alumina in a lower alcohol. The resulting unsubstituted
1,2,3-triazol-4-yl group may then be alkylated as described above.
Compounds of formula (I) in which Z represents a 1-alkyl or
3-alkyl-1,2,3-triazol-4-yl group may be obtained as minor products in the
preparation of the corresponding 2-alkyl-1,2,3-triazol-4-yl compounds and
separated chromatographically.
When Z represents a 2-alkyltetrazol-5-yl group, a Z' cyano group may be
treated with azidotrimethyl silane in an inert solvent such as
tetrahydrofuran at elevated temperature to yield a
2-trimethylsilyl-2H-tetrazol-5-yl group. Treatment of the latter with
methanol effects deprotection of the amino nitrogen which may then be
alkylated as described above.
Compounds of formula (I) in which Z represents a 1-alkyltetrazol-5-yl group
may be obtained as a minor product in the preparation of the corresponding
2-alkyltetrazol-5-yl compound and separated chromatographically.
When Z represents a 1,2,4-triazol-3-yl group a Z' cyano group may be
treated with dry ethanol saturated with hydrogen chloride gas to give an
imidate. This may be treated with an alkyl hydrazine to form the
corresponding amidrazone. Treatment of this with anhydrous formic acid or
triethyl orthoformate will give the required 1-alkyl-1,2,4-triazol-3-yl
group.
When Z represents 3-substituted-1,2,4-oxadiazol-5-yl, an alkoxycarbonyl
group may be reacted with an appropriate amide oxime at elevated
temperature in the presence of sodium alkoxide in a lower alcohol such as
ethanol. The amide oxime is commercially available or may be prepared
conventionally. For example, alkyl substituted amide oximes may be
obtained by reacting hydroxylamine hydrochloride with the appropriate
nitrile.
Alternatively, when Z represents 3-methyl-1,2,4-oxadiazol-5-yl, reaction of
a Z' aminocarbonyl group with an acetal of N,N-dimethylacetamide such as
the dimethyl or diethyl acetal at elevated temperature yields an acyl
amidine group --CON.dbd.C(CH.sub.3)N(CH.sub.3).sub.2 which may then be
reacted with hydroxylamine, in the presence of acid, such as acetic acid,
which may also function as the solvent. The reaction may be carried out at
ambient temperature, the N-hydroxy acyl amidine intermediate optionally
isolated and then cyclised at elevated temperature, or alternatively in a
single step at elevated temperature.
Alternatively and less preferably, a Z' chlorocarbonyl group may be reacted
with an appropriate amide oxime, at elevated temperature in an inert,
polar solvent such as chloroform, and the resulting substitution product
cyclised at elevated temperature in a suitable solvent such as toluene or
xylene.
When Z represents 3-amino-1,2,4-oxadiazol-5-yl, a Z' chlorocarbonyl or,
more preferably, a carboxy ester group A may be reacted with a hydroxy
guanidine derivative under basic conditions.
When Z represents optionally 3-substituted-1,2,4-thiadiazol-5-yl, a Z'
aminocarbonyl group may be converted into an aminothiocarbonyl group using
phosphorus pentasulphide or Lawesson's reagent (S. Scheibye, B. S.
Pederson and J. O. Lawesson, Bull. Soc. Chim. Belg., 1978, 87 (3), 229).
The aminothiocarbonyl may be converted into a thioacyl amidine group and
cyclised as described above for the 1,2,4-oxadiazole group.
When Z represents 5-substituted-1,2,4-oxadiazol-3-yl, a Z' cyano group may
be reacted with hydroxylamine, in a polar solvent such as methanol, to
yield the corresponding amide oxime. The amide oxime may be cyclised using
a suitable derivative of a carboxylic acid such as the anhydride or a
trialkylorthoester such as triethyl orthoacetate, the acid derivative
acting as the solvent, at elevated temperature.
When Z represents optionally 5-substituted-1,3,4-oxadiazol-2-yl, a Z'
carboxy or carboxy ester group A may be converted to the acid hydrazide by
conventional procedures. For example, the acid may be converted to a
C.sub.1-6 alkyl ester e.g. methyl, with the appropriate C.sub.1-6 alkanol
e.g. methanol under conventional esterification conditions, and the
resulting ester reacted with hydrazine at ambient or elevated temperature
to give the acid hydrazide. The acid hydrazide may then be cyclised by
condensation with a suitable derivative of the appropriate carboxylic acid
RCO.sub.2 H, e.g. an acyl halide or a trialkyl ortho-ester, such as the
triethyl ortho-ester, the acid derivative acting as the solvent, at
elevated temperature. Alternatively and preferably, the Z' carboxy ester
group A may be converted to a diacyl hydrazide group --CONHNHCOR by
treatment with the appropriate acyl hydrazide at ambient or elevated
temperature. The diacyl hydrazide may then be cyclised by treatment with
phosphorus pentoxide and methanesulphonic acid.
When Z represents optionally 5-substituted-1,3,4-thiadiazol-2-yl a Z'
diacyl hydrazide group, --CONHNHCOR, obtained as described above can be
cyclised using phosphorus pentasulphide. The cyclisation is preferably
carried out in the absence of solvent with the nitrogen of the azabicycle
protected as the hydrochloride salt.
When Z represents 1,3-oxazol-2-yl, the conversion may be effected by
reaction of a Z' aminocarbonyl group with vinylene carbonate at elevated
temperature in the presence of a strong acid such as polyphosphoric acid,
which may also function as the solvent.
When Z represents optionally 5-substituted-1,3-oxazol-2-yl, a Z' carboxy
group may first be converted to the carboxylic acid chloride and then
reacted with a compound of formula NH.sub.2 CH.sub.2 CR(OR').sub.2, or
more preferably the Z' carboxy group may be reacted directly with the
compound of formula NH.sub.2 CH.sub.2 CR(OR').sub.2 in the presence of a
condensing agent such as dicyclohexylcarbodiimide or a chloroformate ester
such as ethyl chloroformate, to give a group CONHCH.sub.2 C(OR').sub.2 R;
which may be cyclised using a suitable dehydrating agent such as
polyphosphoric acid, phosphorus oxychloride, phosphorus pentachloride,
sulphuric acid or sulphuryl chloride, preferably polyphosphoric acid.
A Z optionally 5-substituted-1,3-thiazol-2-yl group may be obtained by
cyclisation of a Z', --CONHCH.sub.2 C(OR').sub.2 R group using phosphorus
pentasulphide. The reaction is preferably carried out in the absence of
solvent with the nitrogen of the azabicycle protected as the hydrochloride
salt.
1,3-Oxazol-2-yl groups 4-methyl-substituted may be provided by the
cyclisation of a Z' aminocarbonyl group with propargyl alcohol or acetate
ester thereof, in the presence of a dehydrating agent such as
polyphosphoric acid, using a catalyst such as HgSO.sub.4, at elevated
temperature.
Alternative routes to optionally 4-substituted 1,3-oxazol-2-yl groups
include:
i) the condensation of a Z' aminocarbonyl group with the appropriate
compound BrCH.sub.2 COR at elevated temperature; or
ii) the reaction of a Z' carboxy group under basic conditions with the
appropriate compound BrCH.sub.2 COR to give a group --COOCH.sub.2 COR
which may be cyclised with ammonium chloride.
Where R is hydrogen the aldehyde is preferably protected as an acetal.
During the reaction (i) above, the nitrogen atom of the azabicyclic moiety
may require protection.
When Z is optionally 4-substituted-1,3-thiazol-2-yl a Z' aminothiocarbonyl
group may be reacted with the appropriate .alpha.-halo acyl compound such
as BrCH.sub.2 COCH.sub.3 as indicated for the corresponding 1,3-oxazole.
1,3-Oxazol-4-yl groups optionally 2-substituted may be provided by reacting
a bromomethylcarbonyl group with an appropriate amide. Preferably, the
reaction with acetamide is carried out at elevated temperature and the
reaction with formamide is carried out in sulphuric acid.
An unsubstituted 1,3-oxazol-4-yl group may alternatively be obtained by
treatment of a Z' --CH.sub.2 N.sup.+ .tbd.C.sup.- group with a formate
ester such as methyl formate after deprotonation with a strong base such
as n-butyl lithium or potassium t-butoxide.
When Z represents optionally 3-substituted-1,2-oxazol-5-yl, the reaction of
a Z' CH.sub.3 CO group may be carried out at depressed temperature with
the appropriate ethyl ester in a suitable solvent such as toluene, under
basic conditions such as sodium hydride and catalytic ethanol, followed by
reflux, to yield the sodium salt of the resulting dicarbonyl compound.
Cyclisation at ambient temperature with an aminating agent such as
hydroxylamine-0-sulphonic acid in a dry solvent such as methanol, ethanol
or diglyme, preferably in the presence of an acid such as sulphuric acid,
p-toluene sulphonic acid or potassium hydrogen sulphate to minimise
amination of the azabicycle, yields a compound of formula (I).
Alternatively, the dicarbonyl compound sodium salt may be treated prior to
the cyclisation step with dimethylamine in ethanol in the presence of
glacial acetic acid at ambient temperature to give the vinylogous amide
which may be cyclised as described above.
When Z represents an optionally 5-substituted 1,2-oxazol-3-yl group, a Z'
--C.tbd.N.sup.+ --O.sup.- nitrile oxide group may be reacted with an
olefin of the structure R--C(W).dbd.CH.sub.2, where W is halo such as
chloro, OCOCH.sub.3 or OSi(CH.sub.3).sub.3. The highly reactive nitrile
oxide may conveniently be generated in situ from an appropriate Z' halo
oxime --C(Br)=NOH by treatment with a base such as triethylamine in a
solvent such as N,N-dimethylformamide. The halo oxime is prepared by
treatment of a Z'--CH.dbd.NOH oxime group with N-bromosuccinimide in
N,N-dimethylformamide at ambient temperature, the azabicyclic being in the
form of the hydrochloride salt. The Z' --CH.dbd.NOH oxime group may be
prepared from a Z' --CHO group by reaction with hydroxylamine
hydrochloride in a solvent such as methanol.
When Z represents an optionally 2-substituted-1,3-oxazol-5-yl group, a Z'
--COCH.sub.2 Br group may be converted to --COCH.sub.2 NH.sub.2 by
treatment with NaN.sub.3 in acetone or N,N-dimethylformamide followed by
hydrogenation over a Pd/C catalyst in ethanolic HCl, or by treatment with
hexamethylene tetramine followed by hydrolysis in methanolic HCl.
The --COCH.sub.2 NH.sub.2 group may then be acylated with the appropriate
derivative of formic acid such as acetic-formic anhydride or higher
carboxylic acid such as the anhydride or chloride to yield an acyl amino
ketone which can be cyclised using a suitable dehydrating agent such as
polyphosphoric acid, sulphuric acid or phosphorous pentachloride at
elevated temperature.
Alternatively, a Z' --CHO group may be treated with tosylmethyl isocyanide
and anhydrous potassium carbonate in methanol under reflux followed by
heating the 4-methoxyoxazoline product with polyphosphoric acid to afford
a Z 1,3-oxazol-5-yl group.
When Z represents 2-furyl, a Z' CHO group may be treated with a reactive
derivative of propanal such as the 3-tosyl derivative and in which the
carbonyl group is preferably protected as a cyclic acetal (III):
##STR8##
prepared by reaction of sodium 4-methylphenylsulphinate with
2-(2-bromoethyl)-1,3-dioxolane in dimethyl formamide at ambient
temperature. The reaction of the compound of formula (III) with the Z'
--CHO group in an inert solvent such as tetrahydrofuran in the presence of
a base such as n-butyl lithium, initially at low temperature, rising to
ambient, yields a compound of formula (IIIa):
##STR9##
in which A.sub.z represents the azabicyclic moiety, which may be cyclised
at elevated temperature in the presence of an acid such as glacial acetic
acid which may also function as the solvent.
Alkyl-substituted 2-furyl groups may be obtained analogously using the
appropriately substituted analogue of the compound of formula (III)
prepared from the corresponding ketone or aldehyde.
A Z 1,3-thiazol-5-yl group may be obtained by dehydrating and cyclising the
corresponding acyl amino ketone using phosphorous pentasulphide at
elevated temperature.
Optionally 3-substituted 1,2-thiazol-5-yl groups may be prepared from the
corresponding 1,2-oxazolyl group by ring opening effected by treatment
with a reducing agent such as Raney nickel and hydrogen in a suitable
solvent such as methanol or ethanol to yield a vinylogous amide which may
be cyclised using phosphorous pentasulphide in the presence of a suitable
oxidising agent such as sulphur or chloranil in a solvent such as toluene
at elevated temperature.
Compounds of formula (I) in which Q contains a sulphur atom in place of
oxygen may be prepared analogously. A sulphur-containing group Z' is
obtained by treatment of a carbonyl-containing group Z' with either
phosphorus pentasulphide or with Lawesson's reagent (S. Scheibye, B. S.
Pederson and S. O. Lawesson, Bull. Soc. Chim. Belg., 1978, 87(3), 229).
The resulting sulphur-containing group Z' may then be converted to the
required sulphur-containing group Z analogously to the conversion of
carbonyl-containing groups. Where the thiolating agent is phosphorus
pentasulphide, this may also effect cyclisation.
In the above description, R represents H or alkyl as appropriate and R'
represents C.sub.1-6 alkyl such as methyl or ethyl or the R' groups
together represent C.sub.2-6 polymethylene such as ethylene.
Interconversion of carbon substituents R.sub.1, R.sub.2 and R.sub.3 within
a group Z may be carried out conventionally. Thus an amino group may be
converted to chloro, or --NHNH.sub.2, via a diazonium intermediate.
Similarly a chloro substituent may be converted by reaction with a
nucleophile such as methoxide; and alkoxycarbonyl groups may be converted,
via carboxy, to an amino substituent.
When Z represents a --C(R.sub.7).dbd.NR.sub.6 group, a Z' COR.sub.7 group
may be reacted with a compound of formula (IV).
R.sub.6 --NH.sub.2 (IV)
wherein R.sub.6 ' represents R.sub.6 or hydroxy, and thereafter converting
R.sub.6 ' to R.sub.6 when hydroxy.
The invention also provides a process for the preparation of a compound of
formula (I) in which Z is --C(R.sub.7).dbd.NR.sub.6, or a pharmaceutically
acceptable salt thereof, which process comprises reacting a compound of
formula (V):
##STR10##
with a compound of formula (IV):
R.sub.6 '--NH.sub.2 (IV)
wherein R.sub.6 ' represents R.sub.6 or hydroxy, converting R.sub.6 ' to
R.sub.6 when hydroxy, and thereafter forming a pharmaceutically acceptable
salt.
The reaction between the compounds of formulae (V) and (IV) is preferably
carried out in a hydroxylic solvent such as methanol or ethanol, at
ambient temperature, or where appropriate, at elevated temperature.
Where R.sub.6 in compounds of formula (I) is a group OR.sub.8, NHR.sub.10
or NR.sub.11 R.sub.12, a compound of formula (V) is conveniently reacted
with a compound of formula (IV) in which R.sub.6 ' is R.sub.6.
Where R.sub.6 in compounds of formula (I) is a group OCOR.sub.9, a compound
of formula (V) may be reacted with the compound of formula (IV) in which
R.sub.6 ' is hydroxy, with subsequent acylation of the resulting oxime by
treatment with a suitable acylating agent such as an acyl halide, for
example acetyl chloride.
Novel intermediates of formula (VI) and salts thereof:
##STR11##
wherein Z" is a group convertible to Z, also form part of the invention. A
preferred value for Z" is an electron withdrawing group, most preferably
C.sub.1-4 alkoxycarbonyl. Compounds of formula (VI) may be prepared by the
cyclisation of a compound of formula (II) in which R.sub.13 is hydrogen
and A is an electron withdrawing group, the conversion of the resulting Z"
electron withdrawing group to other Z" and optionally forming a salt.
Compounds of formula (II) may be prepared by treatment of a compound of
formula (VII):
##STR12##
wherein R.sub.13 and A are as defined in formula (II), with a compound
L.sup.1 (CH.sub.2).sub.3 L, wherein L is as defined in formula (II) and
L.sup.1 is a leaving group.
In compounds of formula (VII) it is preferred that R.sub.13 is an
N-protecting group and A is cyano. This can be converted to other A
groups, such as C.sub.1-4 alkoxycarbonyl by acid hydrolysis, before
cyclisation of the compound of formula (II).
In the compound L.sup.1 (CH.sub.2).sub.3 L, the leaving group L.sup.1 is
preferably halo and preferably other than L, for example iodo.
The compound of formula (Vll) in which R.sub.13 is benzyl and A is cyano is
described in EP-0169603.
Pharmaceutically acceptable salts of the compounds of formula (I) may be
formed conventionally by reaction with the appropriate acid such as
described above under formula (I).
The compounds of the present invention enhance acetylcholine function via
an action at muscarinic receptors within the central nervous system and
are therefore of potential use in the treatment and/or prophylaxis of
dementia.
The present invention also provides a pharmaceutical composition, which
comprises a compound of formula (I) or pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable carrier.
The compositions may be in the form of tablets, capsules, powders,
granules, lozenges, suppositories, reconstitutable powders, or liquid
preparations such as oral or sterile parenteral solutions or suspensions.
In order to obtain consistency of administration it is preferred that a
composition of the invention is in the form of a unit dose.
Unit dose presentation forms for oral administration may be tablets and
capsules and may contain conventional excipients such as binding agents,
for example syrup, acacia, gelatin, sorbitol, tragacanth, or
polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch,
calcium phosphate, sorbitol or glycine; tabletting lubricants, for example
magnesium stearate; disintegrants, for example starch,
polyvinylpyrrolidone, sodium starch glycollate or microcrystalline
cellulose; or pharmaceutically acceptable wetting agents such as sodium
lauryl sulphate.
The solid oral compositions may be prepared by conventional methods of
blending, filling, tabletting or the like. Repeated blending operations
may be used to distribute the active agent throughout those compositions
employing large quantities of fillers. Such operations are of course
conventional in the art. The tablets may be coated according to methods
well known in normal pharmaceutical practice, in particular with an
enteric coating.
Oral liquid preparations may be in the form of, for example, emulsions,
syrups, or elixirs, or may be presented as a dry product for
reconstitution with water or other suitable vehicle before use. Such
liquid preparations may contain conventional additives such as suspending
agents, for example sorbitol, syrup, methyl cellulose, gelatin,
hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel,
hydrogenated edible fats; emulsifying agents, for example lecithin,
sorbitan monooleate, or acacia; non-aqueous vehicles (which may include
edible oils), for example almond oil, fractionated coconut oil, oily
esters such as esters of glycerine, propylene glycol, or ethyl alcohol;
preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic
acid; and if desired conventional flavouring or colouring agents.
For parenteral administration, fluid unit dosage forms are prepared
utilizing the compound and a sterile vehicle, and, depending on the
concentration used, can be either suspended or dissolved in the vehicle.
In preparing solutions the compound can be dissolved in water for
injection and filter sterilized before filling into a suitable vial or
ampoule and sealing. Advantageously, adjuvants such as a local
anaesthetic, a preservative and buffering agents can be dissolved in the
vehicle. To enhance the stability, the composition can be frozen after
filling into the vial and the water removed under vacuum. Parenteral
suspensions are prepared in substantially the same manner, except that the
compound is suspended in the vehicle instead of being dissolved, and
sterilization cannot be accomplished by filtration. The compound can be
sterilized by exposure to ethylene oxide before suspending in the sterile
vehicle. Advantageously, a surfactant or wetting agent is included in the
composition to facilitate uniform distribution of the compound.
The compositions may contain from 0.1% to 99% by weight, preferably from
10-60% by weight, of the active material, depending on the method of
administration.
The invention also provides a method of treatment and/or prophylaxis of
dementia in mammals including humans, which comprises administering to the
sufferer an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof.
The dose of the compound used in the treatment of such disorders will vary
in the usual way with the seriousness of the disorders, the weight of the
sufferer, and the relative efficacy of the compound. However, as a general
guide suitable unit doses may be 0.05 to 100 mg. for example 0.2 to 50mg;
and such unit doses may be administered more than once a day, for example
two or three times a day, so that the total daily dosage is in the range
of about 0.01 to 5 mg/kg; and such therapy may extend for a number of
weeks or months.
Within the above indicated dosage ranges no toxicological effects are
indicated for the compounds of the invention.
In a further aspect the invention provides a compound of formula (I) or a
pharmaceutically acceptable salt thereof for use as an active therapeutic
substance.
The invention further provides a compound of formula (I) or a
pharmaceutically acceptable salt thereof, for use in the treatment and/or
prophylaxis of dementia.
In another aspect the invention provides the use of a compound of formula
(I) or a pharmaceutically acceptable salt thereof for the preparation of a
medicament for the treatment and/or prophylaxis of dementia.
The following examples illustrate the invention and the following
descriptions illustrate the preparation of intermediates thereto.
DESCRIPTION 1
1-Benzyl-3-(3-chloropropyl)azetidine-3-carbonitrile (D1)
##STR13##
A stirred solution of lithium diisopropylamide (24 ml of 1.5M solution in
cyclohexane, 0.036 mole) and N,N,N',N'-tetramethylethylenediamine (5.4 ml,
0.036 mole) in dry ether (300 ml) at -70.degree. C. under nitrogen was
treated dropwise over 5 minutes with a solution of
1-benzylazetidine-3-carbonitrile* (5.8 g, 0.034 mole) and
1-chloro-3-iodopropane (3.6 ml, 0.034 mole) in ether (40 ml). The
resulting mixture was stirred at -65.degree. C. for 15 minutes, then
allowed to warm up to -40.degree. C. over a further 15 minutes, before
pouring into aqueous potassium carbonate solution (200 ml). The ether
layer was separated and the aqueous further extracted with ethyl acetate
(1.times.150 ml). The two organic solutions were combined, dried (Na.sub.2
SO.sub.4) and concentrated in vacuo to leave an orange oil. This was
purified by column chromatography on silica gel eluting initially with 10%
ether/pentane to remove non-polar impurities and then with 50%
ether/pentane to give the title compound (D1) as a colourless oil (5.35 g,
64%).
*see EP 0 169 603 Al .sup.1 H Nmr (CDCl.sub.3) .delta.: 1.86-2.02 (2H, m),
2.03-2.16 (2H, m), 3.25 (2H, d, J=8Hz), 3.52 (2H, d, J=8Hz), 3.60 (2H, t,
J=7Hz), 3.65 (2H, s), 7.22-7.38 (5H, m).
DESCRIPTION 2
Methyl 1-benzyl-3-(3-chloropropyl)azetidine-3-carboxylate oxalate salt (D2)
##STR14##
A stirred solution of 1-benzyl-3-(3-chloropropyl)-azetidine-3-carbonitrile
(D1, 5.35 g, 0.022 mole) in methanol (75 ml) was treated cautiously with
18 concentrated sulphuric acid (15 ml) and then heated at 80.degree. C.
for 20 h. The solution was cooled in an ice bath and a further 12 ml of
concentrated sulphuric acid added. The solution was heated at 80.degree.
C. for a further 9 hours, then allowed to cool, before pouring cautiously
into ice/water (400 ml) with vigorous stirring. The aqueous mixture was
basified by the addition of 0.88 ammonia solution, then extracted with
ethyl acetate (2.times.200 ml). The combined extracts were dried (Na.sub.2
SO.sub.4) and concentrated in vacuo to leave an orange oil, which was
filtered through a basic alumina column eluting with ether. The colourless
oil obtained was dissolved in ether (150 ml) and treated with a solution
of oxalic acid (2.0 g, 0.022 mole) in methanol (10 ml). The title
compound (D2) was filtered off as a white crystalline solid (7.25 g, 91%).
Free base: .sup.1 H NMR (CDCl.sub.3) .delta.: 1.64-1.80 (2H, m), 2.00-2.13
(2H, m), 3.17 (2H, d, J=8Hz), 3.49 (2H, d, J=8Hz), 3.52 (2H, t, J=7Hz),
3.62 (2H, s), 3.72 (3H, s), 7.20-7.35 (5H, m).
DESCRIPTION 3
Methyl 3-(3-chloropropyl) azetidine-3-carboxylate (D3)
##STR15##
A solution of methyl 1-benzyl-3-(3-chloropropyl)-azetidine-3-carboxylate
oxalate salt (D2, 6.73 g, 0.018 mole) in methanol (800 ml) was
hydrogenated over 10% , palladium on charcoal catalyst (1.4 g) at
40.degree. C. and atmospheric pressure until the uptake of hydrogen
ceased. The reaction mixture was filtered through a pad of kieselguhr and
the filtrate concentrated in vacuo to give a white solid. This material
was treated with excess concentrated potassium carbonate solution (50 ml)
and extracted with chloroform (3.times.70 ml). The combined extracts were
dried (Na.sub.2 SO.sub.4) and concentrated in vacuo to give the title
compound (D3) as a colourless oil (3.3 g, 96%).
.sup.1 H NMR (CDCl.sub.3) .delta.: 1.63-1.78 (2H, m), 2.05-2.15 (2H, m),
2.25 (1H, br.s, NH), 3.42 (2H, d, J=8Hz), 3.53 (2H, t, J=7Hz), 3.73 (3H,
s), 3.96 (2H, d, J=8Hz).
DESCRIPTION 4
Methyl 1-azabicyclo[3.1.11]hept-5-ylcarboxylate oxalate salt (D4)
##STR16##
A solution of methyl 3-(3-chloropropyl)azetidine-3-carboxylate (D3, 3.3 g,
0.017 mole) in propan-2-ol (400 ml) was treated with anhydrous potassium
carbonate (7.5 g, 0.054 mole) and heated under reflux for 18 h. The
mixture was concentrated in vacuo and the residue treated with
concentrated potassium carbonate solution (50 ml) and extracted with ethyl
acetate (2.times.100 ml). The combined extracts were dried (Na.sub.2
SO.sub.4) and concentrated in vacuo to leave a yellow oil (2.6 g), which
was a 1:1 mixture of methyl and isopropyl esters. This was dissolved in
methanol (200 ml), treated with a solution of sodium methoxide (0.045
mole) in methanol (40ml) and stirred at room temperature for 2h. The
solution was cooled in ice, adjusted to pH 4 with methanolic hydrogen
chloride and concentrated in vacuo. The residue was treated with excess
concentrated potassium carbonate solution and extracted with ethyl
acetate. The combined extracts were dried (Na.sub.2 SO.sub.4) and
concentrated in vacuo to leave a yellow oil, which was distilled in a
Kugelrohr apparatus (b.p. approx. 100.degree. C. at 0.2 mmHg) to give 600
mg (23%) of a colourless oil. A portion of this material was converted to
its oxalate salt, which was recrystallised from methanol/ether to give the
title compound (D4) as a white solid m.p. 114.degree.-116.degree. C.
Oxalate salt: .sup.1 H NMR (d6 DMSO) .delta.: 2.08-2.20 (2H, m), 2.20-2.30
(2H, m), 3.35-3.45 (2H, m), 3.47-3.57 (2H, m), 3.65 (3H, s), 4.27-4.37
(2H, m).
.sup.13 C NMR (d.sup.6 DMSO) .delta.: 13.1, 26.6, 44.6, 48.2, 52.6, 57.5,
165.0, 170.5.
Analysis: C.sub.8 H.sub.13 NO.sub.2.C.sub.2 H.sub.2 O.sub.4 ; requires C:
48.98; H: 6.17; N: 5.71; found C: 49.22; H: 6.15; N: 5.84
DESCRIPTION 5
Acetamide oxime (D5)
A solution of sodium methoxide, prepared from 2.90 g (0.126 mole) of
sodium, in methanol (50 ml) was added to a stirred solution of
hydroxylamine hydrochloride (8.7 g, 0.126 mole) in methanol (100 ml). The
mixture was stirred at room temperature for 1h, then filtered and the
filtrate treated with acetonitrile (6.8 ml, 0.13 mole) and heated under
reflux for 6h. A further 6.8 ml of acetonitrile was added and reflux
continued for a further 16 h. The solution was concentrated in vacuo to
give the title compound (D5) as a white solid (7.7 g, 83%) m.p.
123.degree.-127.degree. C.
.sup.1 H NMR (d.sup.6 DMSO) .delta.: 1.60 (3H, s), 5.35 (2H, br.s), 8.60
(1H, s)
DESCRIPTION 6
1-Azabicyclo3.1.11hept-5-ylcarboxaldehyde (D6)
##STR17##
A stirred solution of methyl 1-azabicyclo[3.1.1]hept-5-ylcarboxylate (D4,
800 mg, 0.0052 mole) in dry toluene (15 ml) and hexane (15 ml) at
-65.degree. C. under nitrogen was treated with a 1.5M solution of
diisobutylaluminium hydride in toluene (3.8 ml, 0.0056 mole). The reaction
mixture was stirred at -65.degree. C. for 0.75 h, then poured into excess
1M hydrochloric acid, with vigorous stirring. The mixture was basified
with 10% sodium hydroxide solution, washed with ethyl acetate (1.times.60
ml) and the aqueous solution then saturated with potassium carbonate and
extracted with chloroform (3.times.60 ml). The combined extracts were
dried (Na.sub.2 SO.sub.4) and concentrated in vacuo to give a colourless
oil (620 mg), containing the title compound (D6). This was used without
further purification.
DESCRIPTION 7
Propionamide oxime (D7)
A solution of hydroxylamine hydrochloride (6.90 g, 0.10 mole) in methanol
(100 ml) was added to a stirred solution of sodium methoxide, prepared
from 2.30 g (0.10 mole) of sodium in methanol (40 ml). The mixture was
stirred at room temperature for 1h, then filtered and the filtrate treated
with propionitrile (7.9 ml, 0.11 mole) and heated under reflux for 12 h.
The solution was concentrated in vacuo, the residue shaken with chloroform
(200 ml) and then filtered through Kieselguhr. The filtrate was dried
(Na.sub.2 SO.sub.4) and concentrated in vacuo to give the title compound
(D7) as a colourless oil (5.5 g, 62%).
.sup.1 H NMR (CDCl.sub.3) .delta.: 1.12 (3H, t, J=7Hz), 2.12 (2H, q,
J=7Hz), 4.60 (2H, br.s), 8.60 (1H, br.s).
IR (film) .nu..sub.C.dbd.N 1655cm.sup.-1
DESCRIPTION 8
Butyramide oxime (D8)
The title compound (D8) was prepared from butyronitrile using the method
given in Description 7, as a colourless oil (31%).
.sup.1 H NMR (CDCl.sub.3 +d.sup.6 DMSO) .delta.: 0.95 (3H, t, J=7Hz), 1.60
(2H, sextet, J=7Hz), 2.12 (2H, t, J=7Hz), 4.75 (2H, br.s), 7.25 (1H,
br.s).
DESCRIPTION 9
Cyclopropylcarboxamide oxime (D9)
The title compound (D9) was prepared from cyclopropylcarbonitrile using the
method given in Description 7, as a pale green waxy solid (55%).
.sup.1 H NMR (CDCl.sub.3 +d6DMSO) .delta.: 0.65-0.80 (4H, m), 1.40-1.53
(1H, m), 4.65 (2H, br.s), 8.20 (1H, br.s)
DESCRIPTION 10
Methoxyacetamide oxime (D10)
The title compound (D10) was prepared from methoxyacetonitrile using the
method given in Description 7, as a pale pink solid (100%) m.p.
46.degree.-49.degree. C.
.sup.1 H NMR (CDCl.sub.3) .delta.: 3.35 (3H, s), 3.94 (2H, s), 4.40 (2H,
br.s), 5.00 (1H, br.s)
DESCRIPTION 11
Valeramide oxime (D11)
The title compound (D11) was prepared from valeronitrile using the method
given in Description 7, as a pale green oil (53%).
.sup.1 H NMR (CDCl.sub.3 +d6DMSO) .delta.: 0.92 (3H, t, J=7Hz), 1.30-1.45
(2H, m), 1.50-1.70 (2H, m), 2.20 (2H, t, J=7Hz), 5.40 (2H, br.s), 7.15
(1H, br.s)
DESCRIPTION 12
1-Azabicyclo[3.1.11]hept-5-ylcarboxamide (D12)
##STR18##
ylcarboxylate (D4,
Methyl 1-azabicyclo[3.1 1]hept-5-ylcarboxylate (D4, 1.35 g, 0.0087 mole)
was treated with 20M aqueous ammonia solution (25ml) and the mixture
stirred at room temperature for 2 days. The solution was saturated with
potassium carbonate and shaken with chloroform (40 ml). The mixture
separated into three layers. The chloroform solution contained some
product, however the majority was in the middle layer. These two were
combined and concentrated in vacuo and the residue then treated with
toluene (60 ml) and again concentrated in vacuo to azeotrope out the
water. The title compound (D12) remained as a white solid (1.07 g, 88%)
m.p. 188.degree.-192.degree. C.
.sup.1 H NMR (d.sup.6 DMSO) .delta.: 1.80-1.93 (2H, m), 2.07-2.20 (2H, m),
2.60-2.68 (2H, m), 2.95 (2H, t, J.TM.7Hz), 3.35-3.45 (2H, m), 6.80 (1H,
br.s), 7.05 (1H, br.s)
DESCRIPTION 13
Hexanoamide oxime (D13)
The title compound (D13) was prepared from hexanenitrile using the method
given in Description 7, as a beige solid (73%) m.p. 40.degree.-42.degree.
C.
.sup.1 H NMR (CDCl.sub.3) .delta.: 0.90 (3H, t, J=7Hz), 1.25-1.40 (4H, m),
1.50-1.65 (2H, m), 2.14 (2H, t, J=7Hz), 4.55 (2H, br.s), 8.00 (1H, br.s).
DESCRIPTION 14
E-Pent-3-enamide oxime (D14)
The title compound (D14) was prepared from E-pent-3-enenitrile using the
method given in Description 7, as a yellow oil (55%).
.sup.1 H NMR (CDCl.sub.3 +d.sup.6 DMSO) .delta.: 1.60 (3H, d, J=7Hz), 2.77
(2H, d, J=7Hz), 4.80 (2H, br.s), 5.30-5.45 (1H, m), 5.48-5.65 (1H, m),
7.80 (1H, br.s).
DESCRIPTION 15
N'-Acetyl-1-azabicyclo 3.1.1.1]hept-5-ylhydrazide (D15)
##STR19##
A mixture of methyl 1-azabicyclo[3.1.1]hept-5-ylcarboxylate (D4, 770 mg,
0.0050 mole) and acethydrazide (410 mg, 0.0055 mole) in water (1.2 ml) was
stirred at room temperature for 30 h, then warmed to 50.degree. C. for a
further 8 h. The solution was concentrated in vacuo, using toluene to
azeotrope out the remaining traces of water. The title compound (D15)
remained as a beige solid (980 mg, 100%).
.sup.1 H NMR (CD.sub.3 OD) .delta.: 1.95 (s, 3H), 2.25-2.45 (4H, m),
3.45-3.60 (4H, m), 4.28-4.37 (2H, m), 5.03 (2H, br.s).
DESCRIPTION 16
5-Acetyl-1-azabicyclo [3.1.11]heptane (D 16)
##STR20##
A solution of methyl 1-azabicyclo[3.1.1]hept-5-ylcarboxylate (D4, 1 12 g,
0.0072 mole) in methanol (5 ml) was treated with a solution of lithium
hydroxide monohydrate (308 mg, 0.0073 mole) in water (20 ml) and the
resulting solution stirred at room temperature for 20 h, then concentrated
in vacuo to leave a white solid which was dried thoroughly. A stirred
suspension of this product in dry THF (120 ml) under nitrogen was treated
at room temperature with 1M methyllithium in ether (8.0 ml, 0.0080 mole)
and then heated under reflux for 3.5 h. The mixture was allowed to cool,
then poured into excess well stirred cold 1M hydrochloric acid. The
resulting solution was basified to saturation point with potassium
carbonate and extracted with ethyl acetate (1.times.100 ml), followed by
chloroform (2.times.60 ml). The combined extracts were dried (Na.sub.2
SO.sub.4) and concentrated in vacuo to give the title compound (D 16) as a
yellow oil (360 mg, 36%). This material was used without further
purification.
.sup.1 H NMR (CDCl.sub.3) .delta.: 1.95-2.08 (2H, m), 2.04 (3H, s),
2.16-2.30 (2H, m), 2.79-2.87 (2H, m), 3.17 (2H, t, J=7Hz), 3.70-3.80 (2H,
m)
EXAMPLE 1
5-(3-Amino-1,2,4-oxadiazol-5-yl)-1-azabicyclo[3.1.11]heptane (E1)
##STR21##
A stirred solution of sodium ethoxide (0.019 mole) in ethanol (40 ml) at
room temperature under nitrogen was treated with powdered 3A molecular
sieves (4 g) and methyl 1-azabicyclo[3.1.1]hept-5-ylcarboxylate (D4, 370
mg, 0.0024 mole), followed by hydroxyguanidine hemisulphate hemi-hydrate
(960 mg, 0.0072 mole). The mixture was heated under reflux for 1.25 h,
then cooled in an ice bath and the pH adjusted to 5 by the addition of
glacial acetic acid, before concentrating in vacuo. The residue was shaken
with concentrated potassium carbonate solution (50 ml ) and ethyl acetate
(50 ml ) then filtered through a plug of kieselguhr and the organic layer
separated. The aqueous was extracted with chloroform (2.times.50 ml ) and
all three organic solutions combined, dried (Na.sub.2 SO.sub.4) and
concentrated in vacuo to leave a yellow gum. This was chromatographed on
basic alumina eluting with 20% methanol/ethyl acetate to give the required
material, which was triturated with ether to give the title compound (E1)
as a white solid (32 mg, 7%) m.p. 167.degree.-170.degree. C.
.sup.1 H NMR (CDCl.sub.3) .delta.: 2.00-2.20 (2H, m), 2.48 (2H, t, J=7Hz),
2.98 (2H, dd, J=7Hz and 2Hz), 3.23 (2H, t, J=7Hz), 4.01 (2H, dd, J=7Hz
and 2Hz), 4.55 (2H, br.s, NH.sub.2)
.sup.13 C NMR (CDCl.sub.3) .delta.: 14.5, 29.3, 43.4, 52.7, 59.0, 167.9,
178.9
EXAMPLE 2
5-(3-Methyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo[3.1.1]heptane oxalate salt
(E2)
##STR22##
To a stirred solution of sodium ethoxide, prepared from 390 mg (0.017 mole)
of sodium in ethanol (30 ml ) under nitrogen, was added powdered 3A
molecular sieves (3 g), methyl 1-azabicyclo[3.1.1]hept-5-ylcarboxylate
(D4, 430 mg, 0.0028 mole) and acetamide oxime (D5. 1.03 g. 0.014 mole).
The mixture was heated under reflux for 1 h, then cooled in an ice bath
and adjusted to pH 5 by the addition of glacial acetic acid. The mixture
was concentrated in vacuo and the residue basified with concentrated
potassium carbonate solution, then shaken well with ethyl acetate (100 ml
) and filtered. The organic layer was separated, dried (Na.sub.2 SO.sub.4)
and concentrated in vacuo to leave an orange oil, which was
chromatographed on basic alumina eluting initially with ether and then
with 1:2 ether/ethyl acetate to give a pale yellow oil (290 mg). This was
converted to its oxalate salt and recrystallised from ether/methanol to
give the title compound (E2) as a white solid (270 mg, 6%) m.p.
153.degree.-156.degree. C.
Oxalate salt: .sup.1 H NMR (d.sup.6 DMSO) .delta.: 2.18-2.32 (2H, m), 2.35
(3H, s), 2.50 (2H, t, J=7Hz), 3.51 (2H, t, J=7Hz), 3.75 (2H, dd, J=7Hz and
2Hz), 4.52 (2H, dd, J=7Hz and 2Hz).
.sup.13 C NMR (d.sup.6 DMSO) .delta.: 11.04, 11.06, 13.18, 26.60, 47.92,
58.36, 164.68, 167.02, 176.43
Analysis: C.sub.9 H.sub.13 N.sub.3 O.C.sub.2 H.sub.2 O.sub.4 : requires C:
49.07; H: 5.62; N: 15.61% found C: 48.97; H: 5.62; N: 15.55%
EXAMPLE 3
5-(1,3-Oxazol-5-yl)-1-azabicyc[3.1.1]heptane oxalate salt (E3)
##STR23##
A stirred solution of crude 1-azabicyclo[3.1.1]hept-5-ylcarboxaldehyde (D6,
620 mg, 0.0050 mole) in methanol (15 ml ) was treated with anhydrous
potassium carbonate (830 mg, 0.0060 mole) and tosylmethyl isocyanide (1.07
g, 0.0055 mole). The mixture was heated under reflux for 1.5 h, then
concentrated in vacuo and the residue treated with concentrated potassium
carbonate solution (10 ml ) and extracted with chloroform (3.times.30 ml
). The combined extracts were dried (Na.sub.2 SO.sub.4) and concentrated
in vacuo to leave a yellow oil, which was treated with polyphosphoric acid
(20 g) and heated at 140.degree. C. for 0.25 h. The hot solution was
poured cautiously into excess cold potassium carbonate solution, with good
stirring. The mixture was extracted with ethyl acetate (2.times.50 ml) and
the combined extracts dried (Na.sub.2 SO.sub.4) and concentrated in vacuo
to leave an orange oil. This was chromatographed on basic alumina eluting
with ethyl acetate. The colourless oil obtained was converted to its
oxalate salt and crystallised from methanol/acetone to give the title
compound (E3) as a pale yellow solid (12 mg) m.p. 139.degree.-143.degree.
C.
Oxalate salt: .sup.1 H NMR (CD.sub.3 OD) .delta.: 2.32-2.47 (2H, m),
2.47-2.60 (2H, m), 3.63 (2H, t, J=7Hz), 3.76 (2H, dd, J=7Hz and 2Hz), 4.58
(2H, dd, J=7Hz and 2Hz), 7.15 (1H, s), 8.24 (1H, s).
MS: C.sub.9 H.sub.12 N.sub.2 O requires M.sup.+ =164.0949; found M.sup.+
=164.0951
EXAMPLE 4
5-(1,3-Oxazol-2-yl)-1-azabicvclo[3.1.1]heptane oxalate salt (E4)
##STR24##
A well stirred mixture of 1-azabicyclo[3.1.1]hept-5-ylcarboxamide (D12,
640 mg, 0.0046 mole) and vinylene carbonate (600 mg, 0.0069 mole) in
polyphosphoric acid (25 g) was heated at 120.degree. C. for 1 h. The hot
solution was then poured cautiously, with good stirring, into excess
potassium carbonate solution. The aqueous mixture was saturated with
potassium carbonate and extracted with ethyl acetate (1.times.100 ml ),
followed by chloroform (1.times.100 ml ). The combined extracts were dried
(Na.sub.2 SO.sub.4) and concentrated in vacuo at room temperature. The
residue was immediately chromatographed on basic alumina eluting initially
with ethyl acetate, increasing to 15% methanol/ethyl acetate to give a
colourless oil (60 mg). This was converted to its oxalate salt and
recrystallised from methanol/ether to give the title compound (E4) as a
white solid (65 mg, 6%) m.p. 165.degree.-166.degree. C.
.sup.1 H NMR (d.sup.6 DMSO) .delta.: 2.20-2.33 (2H, m), 2.45-2.55 (2H, m),
3.52 (2H, t. J=7Hz). 3.75 (2H. dd. J=7Hz and 2Hz). 4.47 (2H. dd. J=7Hz and
2Hz), 7.27 (1H. s). B.18 (1H, s).
Analysis: C.sub.9 H.sub.12 N.sub.2 O.C.sub.2 H.sub.2 O.sub.4 : requires C:
51.97: H: 5.55; N: 11.02%; found C: 51.74; H: 5.55; H: 10.73%
EXAMPLE 5
5-(3-Ethyl-1.2.4-oxadiazol-5-yl)-1-azabicyclo[3.1.11]-heptane oxalate salt
(E5)
##STR25##
The title compound (E5) was prepared from methyl
1-azabicyclo[3.1.1]hept-5-ylcarboxylate (D4) and propionamide oxime (D7)
using the method given in Example 2, as a white solid (39%) m.p.
148.degree.-150.degree. C.
Oxalate salt: .sup.1 H NMR (d.sup.6 DMSO) .delta.: 1.24 (3H, t, J=7Hz),
2.17-2.32 (2H, m), 2.45-2.52 (2H, m), 2.74 (2H, q, J=7Hz), 3.50 (2H, t,
J=7Hz), 3.77 (2H, dd, J=7Hz and 2Hz), 4.50 (2H, dd, J=7Hz and 2Hz).
Analysis: C.sub.10 H.sub.15 N.sub.3 O.C.sub.2 H.sub.2 O.sub.4 : requires C:
50.88; H: 6.05; N: 14.83%; found C: 50.66; H: 6.00; N; 14.80%
EXAMPLE 6
5-(3-Propyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo[3.1.11]heptane oxalate salt
(E6)
##STR26##
The title compound (E6) was prepared from methyl
1-azabicyclo[3.1.1]hept-5-ylcarboxylate (D4) and butyramide oxime (D8)
using the method given in Example 2, as a white solid (33%) m.p.
135.degree.-137.degree. C.
Oxalate salt: .sup.1 H NMR (d.sup.6 DMSO) .delta.: 0.93 (3H, t, J=7Hz),
1.69 (2H, sextet, J=7Hz), 2.17-2.32 (2H, m), 2.45-2.55 (2H, m), 2.68 (2H,
t, J=7Hz), 3.50 (2H, t, J=7Hz), 3.76 (2H, dd, J=7Hz and 2Hz), 4.50 (2H,
dd, J=7Hz and 2Hz).
Analysis: C.sub.11 H.sub.17 N.sub.3 O.C.sub.2 H.sub.2 O.sub.4 : requires C:
52.52; H: 6.44; N: 14.13%; found C:52:35; H: 6.44; N: 14.22%
EXAMPLE 7
5-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo-[3.1.1]heptane oxalate
salt (E7)
##STR27##
The title compound (E7) was prepared from methyl
1-azabicyclo[3.1.1]hept-5-ylcarboxylate (D4) and cyclopropylcarboxamide
oxime (D9) using the method given in Example 2, as a white solid (36%)
m.p. 149.degree.-150.degree. C.
Oxalate salt: .sup.1 H NMR (d.sup.6 DMSO) 0.85-0.93 (2H, m), 1.02-1.14 (2H,
m), 2.07-2.30 (3H, m), 2.40-2.53 (2H, m), 3.47 (2H, t, J=7Hz), 3.72 (2H,
dd, J=7Hz and 2Hz), 4.45 (2H, dd, J=7Hz and 2Hz)
Analysis: C.sub.11 H.sub.15 N.sub.3 O.C.sub.2 H.sub.2 O.sub.4 : requires C:
52.88; H: 5.80; N: 14.23; found C: 52.75; H: 5.80; N: 14.06%
EXAMPLE 8
5-(3-Butyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo[3.1.11]heptane oxalate salt
(E8)
##STR28##
The title compound (E8) was prepared from methyl
1-azabicyclo[3.1.1]hept-5-ylcarboxylate (D4) and valeramide oxime (D11)
using the method given in Example 2, as a white solid (37%) m p.
128.degree.-130.degree. C.
Oxalate salt: .sup.1 H NMR (d.sup.6 DMSO) .delta.: 0.88 (3H, t, J=7Hz),
1.25-1.40 (2H, m), 1.55-1.70 (2H, m), 2.15-2.30 (2H, m), 2.45-2.55 (2H,
m), 2.68 (2H, t, J=7Hz), 3.48 (2H, t, J=7Hz), 3.74 (2H, dd, J.TM.7Hz and
2Hz), 4.50 (2H, dd, J=7Hz and 2Hz).
Analysis: C.sub.12 H.sub.19 N.sub.3 O.C.sub.2 H.sub.2 O.sub.4 : requires C:
54.01; H: 6.80; N: 13.50%; found C: 53.88; H: 6.87; N: 13.28%
EXAMPLE 9
5-(3-Methoxymethyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo-[3.1.11]heptane
oxalate salt (E9)
##STR29##
A stirred solution of sodium methoxide, prepared from 290 mg (0.012 mole)
of sodium in methanol (20 ml ), under nitrogen was treated with methyl
1-azabicyclo[3.1.1]-hept-5-ylcarboxylate (D4, 300 mg, 0.0019 mole),
methoxyacetamide oxime (D10, 1.0 g, 0.0097 mole) and powdered 3A molecular
sieves (2.5 g). The mixture was heated under reflux for 3.5h, then cooled
in an ice bath and adjusted to pH 6 by the addition of glacial acetic
acid. The mixture was concentrated in vacuo and the residue basified with
concentrated potassium carbonate solution, then shaken with ethyl acetate
(100 ml ). The mixture was filtered and the organic layer separated, dried
(Na.sub.2 SO.sub.4) and concentrated in vacuo to leave a yellow oil. This
material was chromatographed twice on basic alumina, each time eluting
initially with ether then with 20% ethyl acetate/ether to eventually give
a colourless oil (80 mg). This was converted to its oxalate salt and
crystallised from acetone to give the title compound (E 9) as a white
solid (12%) m.p. 102.degree.-104.degree. C.
Oxalate salt: .sup.1 H NMR (d.sup.6 DMSO) .delta.: 2.15-2.30 (2H, m),
2.47-2.55 (2H, m), 3.33 (3H, s), 3.50 (2H, t, J=7Hz), 3.77 (2H, dd, J=7Hz
and 2Hz), 4.53 (2H, dd, J=7Hz and 2Hz), 4.55 (2H, s).
EXAMPLE 10
5-(3-Pentyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo[3.1.1]heptane oxalate salt
(E10)
##STR30##
The title compound (E10) was prepared from methyl
1-azabicyclo[3.1.1]hept-5-yl-carboxylate (D4) and hexanoamide oxime (D13)
using the method given in Example 2, as a white solid (32%) m.p.
127.degree.-129.degree. C.
Oxalate salt: .sup.1 H NMR (d.sup.6 DMSO) .delta.: 0.87 (3H, t, J=7Hz),
1.25-1.40 (4H. m), 1.57-1.73 (2H, m), 2.15-2.30 (2H, m), 2.45-2.55 (2H,
m), 2.68 (2H, t, J=7Hz), 3.50 (2H, t, J=7Hz), 3.75 (2H, dd, J=7Hz and
2Hz), 4.50 (2H, dd, J=7Hz and 2Hz).
Anaylsis: C.sub.13 H.sub.21 N.sub.3 O.C.sub.2 H.sub.2 O.sub.4 : requires C:
55.37: H: 7.13; N 12.92%; found C: 55.53; H: 7.16; N: 12.91%
EXAMPLE 11
E-5-(3-But-2-enyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo-[3.1.11]heptane
oxalate salt (E11)
##STR31##
Methyl 1-azabicyclo[3.1.1]hept-5-ylcarboxylate (D4) was treated with
E-pent-3-enamide oxime (D14) using the procedure described for Example 2.
The crude product was purified by chromatography on basic alumina eluting
initially with 1:1 ether/pentane and then with neat ether to give a
colourless oil. This was converted to its oxalate salt and recrystallised
from methanol/ether to give a white solid (25%) containing 90% of the
title compound (Ell) and 10% of the corresponding 1-butene isomer. m.p.
132.degree.-135.degree. C.
Oxalate salt:
.sup.1 H NMR (d.sup.6 DMSO) .delta.: (major isomer) 1.64 (3H, d, J=7Hz),
2.16-2.32 (2H, m), 2.43-2.57 (2H, m), 3.40-3.57 (4H, m), 3.75 (2H, dd,
J=7Hz and 2Hz), 4.48 (2H, dd, J=7Hz and 2Hz), 5.48-5.74 (2H, m).
.sup.13 C NMR (d.sup.6 DMSO) .delta.: (major isomer) 13.22, 17.66, 26.66,
28.64, 38.96, 47.96, 58.41, 124.30, 128.76, 164.78 (COOH).sub.2, 169.16,
176.65.
EXAMPLE 12
5-(Fur-2-yl)-1-azabicyclo[3.1.1]heptane (E12)
##STR32##
A stirred solution of lithium diisopropylamide (4.0 ml of 1 5M cyclohexane
solution; 0.0060 mole) in dry tetrahydrofuran (100 ml ) at -65.degree. C.
under nitrogen was treated with a solution of
2-[2-(4-methylphenylsulphonyl)ethyl ]-1,3-dioxolane (compound D5 in
EP-0322182, 1.54 g, 0.0060 mole) in dry tetrahydrofuran (5 ml). After
stirring the resulting solution at -65.degree. C. for 10 minutes, a
solution of crude 1-azabicyclo[3.1.1]hept-5-ylcarboxaldehyde (D6, 550 mg,
0.0044 mole) in dry THF (8 ml ) was added. The reaction mixture was
allowed to warm up to -20.degree. C. over 30 minutes, then treated with
glacial acetic acid (5 ml ) and concentrated in vacuo. The residue was
dissolved in glacial acetic acid (100 ml ), treated with
4-toluenesulphonic acid (20 mg) and heated under reflux for 24 h. The
solution was concentrated in vacuo and the residue basified with
concentrated potassium carbonate solution and extracted with chloroform
(2.times.80 ml ). The combined extracts were dried (Na.sub.2 SO.sub.4) and
concentrated in vacuo to leave a brown oil, which was distilled in a
Kugelrohr apparatus. The material boiling at 130.degree.-150.degree. C. at
0.1 mmHg was collected and then chromatographed on basic alumina eluting
initially with ether to remove impurities, then with 10% methanol/ethyl
acetate to remove the title compound (E12), which was obtained as a
colourless oil (4 mg).
.sup.1 H NMR (CDCl.sub.3) .delta.: 1.93-2.08 (2H, m), 2.25-2.35 (2H, m),
2.84-2.94 (2H, m), 3.17 (2H, t, J=7Hz), 3.86-3.95 (2H, m), 5.92-5.95 (1H,
m), 6.20-6.25 (1H, m), 7.25-7.28 (1H, m).
EXAMPLE 13
5-(2-Methyl-1,3,4-oxadiazol-5-yl)-1-azabicyclo[3 1.1]heptane oxalate salt
(E13)
##STR33##
A mixture of phosphorus pentoxide (2.8 g, 0.025 mole) and methanesulphonic
acid (28 g, 0.25 mole) was stirred at room temperature for 1 h, then added
to N'-acetyl-1-azabicyclo[3.1.1]hept-5-ylhydrazide (D15, 980 mg, 0.0050
mole) and the mixture heated at 70.degree. C. for 2 h. The solution was
allowed to cool, then added carefully to excess cold concentrated
potassium carbonate solution, with good stirring. The mixture was
extracted with chloroform (2.times.70 ml ), and the combined extracts
dried (Na.sub.2 SO.sub.4) and concentrated in vacuo to leave a yellow oil.
This was chromatographed on basic alumina eluting with 10% methanol/ethyl
acetate and the colourless oil obtained converted to its oxalate salt.
This was recrystallised from methanol/ether to give the title compound
(E13) as a white solid (190 mg, 14%) m.p. 149.degree.-150.degree. C.
Oxalate: .sup.1 NMR (d.sup.6 DMSO) .delta.: 2.18-2.32 (2H, m), 2.43-2.57
(2H, m), 2.48 (3H, s), 3.50 (2H, t, J=7Hz), 3.76 (2H, dd, J=7Hz and 2Hz),
4.47 (2H, dd, J=7Hz and 2Hz).
Analysis: C.sub.9 H.sub.13 N.sub.3 O.C.sub.2 H.sub.2 O.sub.4 ; requires C:
49.07; H: 5.62; N: 15.61%; found C: 48.93; H: 5.63; N: 15.83%
EXAMPLE 14
E-1-Azabicyclo[2.1.1]hept-5-ylcarboxaldehyde-O-methyloxime oxalate salt
(E14)
##STR34##
A solution of crude 1-azabicyclo[3.1.1]hept-5-ylcarboxaldehyde (D6, 0.0026
mole) in methanol (15 ml ) was treated with O-methylhydroxylamine
hydrochloride (220 mg, 0.0026 mole) and the resulting solution left to
stand for 2 days at room temperature. The solution was concentrated in
vacuo, the residue basified with concentrated potassium carbonate solution
and extracted with chloroform (2.times.50 ml ). The combined extracts were
dried (Na.sub.2 SO.sub.4) and concentrated in vacuo to leave a pale yellow
oil, which was chromatographed on basic alumina eluting with 10%
methanol/ethyl acetate. The colourless oil obtained was converted to its
oxalate salt and recrystallised from methanol/ether to give the title
compound (E14) as a white solid (80 mg, 13%) m.p. 126.degree.-129.degree.
C.
Oxalate salt: .sup.1 H NMR (d.sup.6 DMSO) .delta.: 2.05-2.20 (4H, m),
3.38-3.53 (4H, m), 3.75 (3H, s), 4.15-4.25 (2H, m), 7.47 (1H, s).
Analysis: C.sub.8 H.sub.14 N.sub.2 O.C.sub.2 H.sub.2 O.sub.4 : requires C:
49.18; H: 6.60; N: 11.47%; found C: 49.08; H: 6.65; N: 11.36%
The hydrochloride salt is obtained analogously from the free base using
hydrogen chloride in ether.
EXAMPLE 15
E and Z-5-Acetyl-1-azabicyclo[3.1.1]heptane O-methyloxime oxalate salt
(E15)
##STR35##
A stirred solution of 5-acetyl-1-azabicyclo[3.1.1]heptane (D16, 360 mg,
0.0026 mole) in methanol (20 ml ) was treated with O-methylhydroxylamine
hydrochloride (250 mg, 0.0030 mole) and left at room temperature for 20 h.
The solution was concentrated in vacuo and the residue basified with
concentrated potassium carbonate solution and extracted with chloroform
(2.times.60 ml ). The combined extracts were dried (Na.sub.2 SO.sub.4) and
concentrated in vacuo to leave a brown oil, which was chromatographed on
basic alumina eluting with 5% methanol/ethyl acetate. The pale yellow oil
obtained was converted to its oxalate salt and crystallised from
methanol/ether to give the title compound (E15) as a 2:3 mixture of E:Z
isomers, as a white solid (110 mg, 14%) m.p. 110.degree.-116.degree. C.
Oxalate salt: .sup.1 H NMR (2:3 mixture of E/Z isomers) (d.sup.6 DMSO)
.delta.: 1.70 and 1.71 (together 3H, 2 x s), 2.05-2.20 (4H, m), 3.35-3.45
(2H, m), 3.47-3.60 (2H, m), 3.67 (s, CH.sub.30, Z-isomer), 3.76 (s,
CH.sub.3 O, E-isomer), 4.13-4.25 (2H, m)
BIOLOGICAL ACTIVITY
Radio ligand Binding
Cerebral cortex from Hooded Lister rats (Olac, UK) is homogenised in 2.5
vols ice-cold 50mM tris buffer pH 7.7 (at 25.degree. C.) After
centrifugation at 25,000 .times.g at 4.degree. C. for 15 min the pellet is
resuspended in 2.5 vols buffer and the wash repeated 3 times more. The
final resuspension is in 2.5 volumes and the homogenates are stored in 1
ml aliquots at -20.degree. C.
Incubations (total volume 2 ml ) are prepared using the above buffer with
the addition of 2mM magnesium chloride in the 3H-Oxotremorine-M (3H-OXO-M)
experiments. For 3H-Quinuclidinyl Benzilate (3H-QNB), 1 ml of stored
membranes is diluted to 30 ml and 0.1 ml mixed with test compound and
0.27nM (c. 25,000 cpm) 3H-QNB (Amersham International). For 3H-OXO-M, lml
of membranes is diluted to 6 ml and 0.lml mixed with test compound and 2
nM (c. 250,000 cpm) 3H-OXO-M (New England Nuclear).
Non-specific binding of 3H-QNB is defined using 1.mu.M Atropine sulphate
(2.mu.M Atropine) and of 3H-OXO-M using 10.mu.M Oxotremorine. Non-specific
binding values typically are 5% and 25% of total binding, respectively.
Incubations are carried out at 37.degree. C. for 30 min and the samples
filtered using Whatman GF/B filters. (In the 3H-OXO-M experiments the
filters are presoaked for 30 min in 0.05% polyethylenimine in water).
Filters are washed with 3.times.4 ml ice-cold buffer. Radioactivity is
assessed using a Packard BPLD scintillation counter, 3 ml Pico-Fluor 30
(Packard) as scintillant.
This test provides an indication of the muscarinic binding activity of the
test compound. The results are obtained as IC.sub.50 values (i.e. the
concentration which inhibits binding of the ligand by 50%) for the
displacement of the muscarinic agonist 3H-OXO-M and the muscarinic
antagonist 3H-QNG. The ratio IC.sub.50 (3H-QNB)/IC.sub.50 (3H-OXO-M) gives
an indication of the agonist character of the compound. Agonists typically
exhibit a large ratio; antagonists typically exhibit a ratio near to
unity.
The results are shown in Table 1.
TABLE 1
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.sup.3 H-OXO-M
.sup.3 H-QNB
Example IC.sub.50 (nM)
IC.sub.50 (nM)
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E1 11 11000
E2 15 5000
E3 37 6250
E4 540 60000
E5 71 5200
E6 40 1700
E7 62 580
E8 49 1950
E9 178 13000
E10 141 2400
E11 165 1850
E13 207 16500
E14 109 24000
E15 290 58000
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